This study assessed the effect of fluoxetine 20 mg/day on weight loss in older patients treated for major depression in a multicenter, double-blind placebo-controlled, 6-week clinical trial. Thirty U.S. outpatient clinics affiliated with psychiatric programs participated in the study that involved 671 medically stable outpatients at least 60 years old who had normal cognition and met DSM-III-R criteria for major depression. Weight was recorded at weekly visits. As a measure of adiposity, patients were categorized into two groups, high and low/normal body mass index (BMI) groups. Analyses were done for each group. The high BMI group, but not the low/normal BMI group, had a statistically greater proportion of fluoxetine-treated patients who lost at least 5% of their baseline weight. Overall mean weight change for the fluoxetine-treated patients was about 1% compared with essentially no change for placebo-treated patients. Only one patients, who was treated with fluoxetine and in the low/normal BMI group, discontinued from the study because of weight loss. Although 5% weight loss occurred in more fluoxetine-treated than placebo-treated patients, most of the patients who lost weight had higher adiposity at baseline. There was not a statistically significant difference in the proportion of fluoxetine-treated and placebo-treated patients in the low/normal group who had at least 5% weight loss. Medically relevant weight loss in older patients treated with fluoxetine was uncommon.